PDK-1/S6K and mTORC1 bypass systemic growth restrictions to promote regeneration

Tissue damage and inflammation trigger systemic signals that induce catabolic breakdown and nutrient release in distant organs, a process well-characterized in the context of tumor cachexia. While mechanisms allowing tumors to circumvent these systemic growth restrictions are known, the physiological processes that overcome inflammation-induced growth restrictions to support tissue repair and regeneration remain largely unexplored. In our study, we use a model of tissue inflammation and regeneration in developing Drosophila imaginal discs to dissect the key metabolic and signaling adaptations that help tissue overcome systemic growth restrictions. Our findings reveal a unique metabolic strategy used by rapidly proliferating cells in the regenerating domain. Instead of relying on the conventional Insulin-PI3K-Akt signaling pathway, these cells utilize a JAK/STAT-PDK1-S6K axis. This adaptation facilitates sustained protein synthesis and cellular growth despite the systemic catabolism associated with low insulin signaling. Specifically, we find that catabolic breakdown of the fat body is driven by the insulin-binding factor Impl2, which is expressed at the site of inflammatory damage. Notably, regenerative proliferation is also supported by mTORC1 activity and is associated with the upregulation of amino acid transporters in proliferating cells of the regenerating domain. These amino acid transporters align with a specific amino acid metabolite signature in the hemolymph, revealing a specialized metabolic program that meets the demands of fast-proliferating cells. Our work provides insight into how regenerating tissues rewire signaling pathways and adapt their metabolic growth to coordinate tissue repair with a conserved systemic nutrient provision response. These findings have important implications for understanding human diseases such as chronic wounds and cancer. ### Competing Interest Statement The authors have declared no competing interest.